Epithelial cell ovarian cancer EOC constitutes 90% of ovarian can-cers, while gonadal-stromal 6% occurrence, and germ cell 4% occurrence tumors make up the rest of the incidence of ovari
Trang 1R E V I E W Open Access
The detection, treatment, and biology of
epithelial ovarian cancer
Jennifer AA Gubbels1, Nick Claussen2, Arvinder K Kapur2, Joseph P Connor2*, Manish S Patankar2*
Abstract
Ovarian cancer is particularly insidious in nature Its ability to go undetected until late stages coupled with its non-descript signs and symptoms make it the seventh leading cause of cancer related deaths in women Additionally, the lack of sensitive diagnostic tools and resistance to widely accepted chemotherapy regimens make ovarian can-cer devastating to patients and families and frustrating to medical practitioners and researchers Here, we provide
an in-depth review of the theories describing the origin of ovarian cancer, molecular factors that influence its growth and development, and standard methods for detection and treatment Special emphasis is focused on interactions between ovarian tumors and the innate and adaptive immune system and attempts that are currently underway to devise novel immunotherapeutic approaches for the treatment of ovarian tumors
Ovarian cancer occurrence
Epithelial ovarian cancer (EOC) is the most deadly of
gynecological cancers and is the seventh-leading cause
of cancer deaths in women In 2008, there were 21,650
cases reported which resulted in the deaths of 15,520
women in the United States [1] Spread of the disease
within the peritoneal cavity is associated with
non-speci-fic clinical symptoms that are often mistaken for other
gastrointestinal or reproductive diseases Some of the
most common symptoms are abdominal discomfort and
bloating Other symptoms include vaginal bleeding,
gas-trointestinal discomfort, early satiety, and urinary tract
symptoms [2] Another obstacle hindering diagnosis is
the fact that the ovaries are deep within the pelvic cavity
and difficult to palpate, especially in peri-post
menopau-sal women, the group with the highest incidence of the
disease Because of these reasons, 70% of patients are
not diagnosed with the disease until the cancer has
metastasized beyond the ovaries and is at stage III or IV
[3] However, studies surveying ovarian cancer patients
demonstrate that over 95% of EOC patients had
abdom-inal complaints for many months before their diagnosis
[4-6] There is now a new initiative to quantify the
symptoms experienced by ovarian cancer patients prior
to diagnosis of the disease A “Symptoms Index” has
been established and studies are underway to determine
if it can be used- either independently or in combina-tion- with a molecular marker as a predictor of early stage ovarian cancer [5,6]
There are several different types of ovarian cancers depending upon the cell type of origin Epithelial cell ovarian cancer (EOC) constitutes 90% of ovarian can-cers, while gonadal-stromal (6% occurrence), and germ cell (4% occurrence) tumors make up the rest of the incidence of ovarian cancer patients [7] As ovarian can-cer of epithelial cell origin is the most common type, EOC is discussed throughout this review
The majority of EOC cases are sporadic in nature and occur in women with no known predisposing factors and thus, in the general population, the overall risk of EOC is low (2-5%) Only a small percentage (5-10%) of EOC patients have a genetic predisposition to the dis-ease Ninety percent of these patients are carriers of mutated BRCA1 and/or BRCA2 genes, which are also implicated in hereditary breast cancer [8] These genes normally act as tumor suppressors and regulate cellular proliferation and DNA repair by maintaining chromo-some integrity Mutations in these genes render the pro-teins unable to perform their intended functions The lifetime risk of ovarian cancer for patients with BRCA1 mutations is 20% to 60%, and the risk for BRCA2 muta-tion carriers is 10% to 35% [8] Ovarian cancers asso-ciated with germline mutations of BRCA1 appear to be predominantly of serous type and age of the patient at diagnosis is significantly less as compared to the
* Correspondence: jpconnor@wisc.edu; patankar@wisc.edu
2 Department of Obstetrics and Gynecology, University of Wisconsin-Madison,
600 Highland Ave, Madison, WI, 53792, USA
© 2010 Gubbels et al; licensee BioMed Central Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
Trang 2sporadic ovarian cancers [9,10] Women who have this
mutation may elect to undergo prophylactic bilateral
sal-pingo-oophorectomy (removal of both fallopian tubes
and ovaries)
Origins of EOC
The normal ovarian surface epithelium (OSE) covers the
surface of the ovary OSE is highly responsive to
envir-onmental stimuli, including those associated with
ovula-tion [11] In a normal woman, OSE are a monolayered
squamous-to-cuboidal epithelium which functions to
shuttle molecules in and out of the peritoneal cavity, as
well as participates in the rupture and repair that
accompanies every ovulation [12] These cells are
mor-phologically indistinct and histologically simple;
there-fore, it is difficult to understand how these cells can
transform into tumors [13] The OSE derive from the
embryonic celomic epithelial cells which are a part of
the mesoderm The fallopian tube, uterus, and
endocer-vix are derived from the Mullerian duct which is an
invagination of the celomic epithelium It is
hypothe-sized that OSE cells retain the ability to differentiate
into four major histological subtypes, which could
explain the distinct histological EOC subtypes There
are four common sub-types of EOC including serous
(fallopian tube-like), endometrioid (endometrium-like),
mucinous (endocervical-like), and clear cell
(mesone-phros-like) [12]
The differentiation of OSE cells from cuboidal
epithe-lial cells to a mesenchymal phenotype that is
character-istic of Mullerian duct-derived tissues is termed
epithelial- mesenchymal transition (EMT) The
occur-rence of EMT is postulated to aid cells in movement
during embryo tissue generation, tissue regeneration
after wounding, and is implicated in the development of
cancer [14] OSE cells normally undergo EMT to heal
the wound that forms following ovulation Uncommitted
OSE cells normally express keratin, which is associated
with an epithelial cell type [12] However, these cells
also constitutively express vimentin, N-cadherin, and
smooth muscle alpha-actin, all of which are associated
with the mesenchymal phenotype [12] OSE cells also
produce several proteolytic enzymes (which help to
degrade the epithelial cell wall during ovulation), as well
as secrete collagen type III, characteristics that are also
common to mesenchymal cells OSE cells express low
levels of the mucin MUC16 (CA125) Mullerian-duct
derived tissues express high levels of MUC16 (CA125),
as do ovarian tumors [15] As we will discuss later,
MUC16 (CA125) over expression in ovarian tumors is
an important marker for progression and regression of
EOC
OSE cells undergo EMT transition after ovulation
to remodel the extracellular matrix and repair the
post-ovulatory wound that is generated during expulsion
of the oocyte Epithelial cells are characteristically polar and are bound together with molecules (such as E-cadherin) that facilitate cell-cell junctions Conversely, the mesenchymal phenotype is that of motility and movement, as well as reduced polarity of a cell [16] The transition of OSE to a mesenchymal phenotype aids
in the ovulatory process because these converted cells have increased motility, altered proliferative responses, and the ability to remodel the extracellular matrix (ECM) [17] TGF-b, EGF, and collagen are all present at the site of ovulatory rupture and can induce OSE EMT OSE cells also undergo EMT in collagen matrices It is a normal function of OSE to undergo EMT, therefore, cancer may represent unregulated EMT [14]
The expression of markers that are associated with those of Mullerian-duct derived tissue are found in inclusion cysts, which are the site of many neoplasms OSE lining inclusion cysts express higher levels of EOC markers MUC16 (CA125) and CA19-9 and is two to three times more metaplastic in women with ovarian tumors compared to OSE in normal ovaries [18] The hypothesis that EOC may derive from inclusion cysts is based upon the incessant ovulation theory, first pro-posed by Fathalla in 1971 [19] This theory is based upon epidemiological data that reveals that women on birth control or who have been pregnant and/or breast-feeding have decreased risk of ovarian cancer Fathalla suggested that wounds in the epithelium surrounding the ovary caused by ovulation month after month can cause increased inflammation and cell proliferation; thereby increasing the chance for cells to form neo-plasms Higher ovulatory activity is associated with an increased accumulation of inclusion cysts and invagina-tions of the OSE, which provide a hospitable environ-ment for tumor cell growth [20] This concept is supported by in vitro evidence in which ovarian surface epithelial cells from both rats and mice have been con-tinuously cultured, mimicking the constant damage and repair that OSE undergo In both species these in vitro cells spontaneously transformed into cancerous cells [21-23] Another observation that supports the incessant ovulation hypothesis is that studies have repeatedly shown that oral contraceptive use (which prevents ovu-lation) reduces ovarian cancer risk [24]
An alternative hypothesis related to that of incessant ovulation is known as the gonadotropin hypothesis [25-27] High levels of gonadotropins initiate each ovu-lation and persist immediately after menopause These hormones stimulate the ovulation-like process involving the expression of cytokines and proteolytic enzymes within the surface epithelium I nflammatory factors may lead to a loss of the basement membrane and the formation of inclusion cysts which can contribute to cell
Trang 3transformation into cancer [20] One animal model
(ewes) showed that oxidants released during ovulation
caused DNA fragmentation and apoptosis in cells that
were closest to the rupture, while milder DNA damage
and the accumulation of p53 was shown in decreasing
levels farther away from the rupture site [28]
Others hypothesize that ovarian tumors do not arise
from OSE at all, but derive directly from the
Mullerian-duct tissues and migrate to the ovarian surface Dubeau
first proposed this hypothesis in 1999 [29] According to
Dubeau, the theory which suggests that OSE cells must
first differentiate into Mullerian-duct type cells via
metaplasia before becoming neoplastic contradicts our
current understanding of cancer, which is that the
can-cerous cells are less differentiated than the cells they
originate from [30] He suggests that a more likely
sce-nario is that EOC derives from Mullerian-duct derived
tissues, and has several compelling observations to
sup-port this hypothesis Ovarian tumor cells share many
similar characteristics to the cells of the fallopian tubes,
uterus, and endocervix, and do not share histological or
protein expression profile with the OSE Dubeau argues
that the fimbrae of the fallopian tubes, which literally
rub up against the surface of the ovary during ovulation
and sometimes adhere to the surface of the ovary due to
inflammation, are a prime site for the development of
metaplasia The cells from the fimbrae of the fallopian
tubes have been shown to have developed pre-neoplastic
changes in women who have undergone surgery for
pro-phylactic removal of their fallopian tubes because of a
mutation in BRCA1 [31-33]
In addition to histological changes found in the
fim-brae of the fallopian tubes, mutations in the tumor
sup-pressor gene p53 in the distal fimbrae of women with
the BRCA+ mutation have also been observed [34]
Christopher Crum’s group found strong p53 staining in
benign tissues from BRCA+women who underwent
pro-phylactic salpingo-oophorectomies This staining
corre-lated with mutations in the p53 gene in these same
cells Because the p53 mutations were found
predomi-nantly in the distal fimbrae of the fallopian tubes (the
cells that are in contact with the OSE), the location of
this staining may reveal one mechanism by which
ovar-ian tumors arise in BRCA+ women [34] In 2008,
Crum’s group correlated the p53 mutation in the
fallo-pian tube fimbrae with lower parity and increased age at
first childbirth, which links this marker to incessant
ovulation [35] A comparison of p53 mutations in
ovar-ian inclusion cysts with p53 mutations in the fimbrae of
fallopian tubes, again from women who were BRCA+
was conducted The results revealed that p53 mutations
were not present in any inclusion cysts that were
exam-ined, but were present in 38% of fimbrae of fallopian
tubes from these women [36] Another piece of evidence
to support the argument that EOC arises from the fallo-pian tube is that several studies have shown that tumor cells clinically identical to ovarian cancer cells are found
in the peritoneal environment in women years after their ovaries have been removed for reasons other than cancer [37-39]
Dubeau states that ovarian cancer is over-diagnosed, and many of these cancers actually arise from the fallo-pian tube or peritoneal cavity wall The origin of ovarian tumors is of important consideration, not only for nomenclature reasons, but for women who have the BRCA1 or BRCA2 mutation and are undergoing pro-phylactic surgery and who want to preserve their ferti-lity If the origin of ovarian cancer is indeed not the ovary, then the ovaries need not be removed, and cryo-preservation of oocytes for future use is not an issue [30]
Ovarian cancer detection Attempts to find an accurate screening test for EOC have, to date, been unsuccessful CA125 (MUC16), ori-ginally thought to be an indicator of ovarian cancer, is now known to be quite non-specific as well as to lack the sensitivity to detect stage I disease Bast and cowor-kers showed in the 1980s that CA125 was expressed in the serum of the majority of patients with EOC, as well
as patients with cancer of the endometrium, fallopian tube, and endocervix [40-44] CA125 serum levels are elevated in 80% of advanced stage EOC patients; how-ever, this marker can be elevated in a variety of benign conditions and other non-gynecologic malignancies High concentrations are found in pancreatic, breast, bladder, liver, and lung cancers, as well as benign diseases such as diverticulitis, uterine fibroids, endome-triosis, benign ovarian cyst, tubo-ovarian abscess, hyperstimulation syndrome, and ectopic pregnancies [42,45-48] Elevated levels are also found in physiological conditions including both normal pregnancy and men-struation [49] Furthermore, CA125 levels are elevated
in less than half of the cases in early-stage ovarian can-cers, underscoring the lack of sensitivity to diagnose curable disease Therefore, CA125 is not used as a screening test, but mainly as a measure of disease pro-gression, repro-gression, and predictor of recurrence during treatment for EOC CA125 levels measured over a per-iod of time along with transvaginal sonography has been shown to increase sensitivity [50], however, the cost of transvaginal screening limits its use in the general popu-lation CA125 itself is a repeating peptide epitope on the large molecular weight mucin, MUC16 [51-54] This mucin is expressed at low levels by normal ovarian sur-face epithelium and is overexpressed by EOC tumor cells [43,49] Tumor cells secrete MUC16 into the peri-toneal fluid (PF) and from the abdominal cavity this
Trang 4mucin leaks into the blood stream and can then be
detected via the CA125 serum assay
Proteomic approaches are being utilized to identify
molecular markers for ovarian cancer and mathematical
models are being developed to identify specific patterns
that are indicative of disease [55] Other promising
mar-kers for ovarian cancer include human epididymis
pro-tein-4 (HE4), decoy receptor-3 (DcR3), osteopontin,
mesothelin, spondin-2, SMRP, CA72-4, ERBB2, inhibin,
activin, EGFR, and lysophosphatidic acid, [50,56-66] Of
these the most promising is HE4 which is expressed on
ovarian tumor cells from some patients that do not
express CA125 Indeed, studies have shown that the
combined monitoring of serum levels of CA125 and
HE4 is likely to significantly improve the sensitivity for
detection of ovarian cancer in women with pelvic mass
[67] An important study published recently has
con-cluded that a steady increase in the serum
concentra-tions of CA125, HE4, and mesothelin can be detected in
patients up to 1-3 years before a clinical diagnosis of
ovarian cancer is made in patients [68]
Ovarian cancer staging and treatment
Ovarian cancer is a surgically staged disease, meaning
that it is impossible to tell what the stage of the cancer
is without examining the extent of the metastasis
surgi-cally Metastasis of ovarian cancer spreads by direct
extension to neighboring organs from the ovaries or by
the sloughing of tumor cells into the peritoneal cavity
These individual or groups of exfoliated cells float in the
fluid of the peritoneal cavity and can subsequently bind
to the wall of the peritoneal cavity and form additional
lesions The tumor cells also commonly disseminate by
lymphatic spread [69] Proper surgical staging requires a
complete inspection of the peritoneal cavity and its
con-tents, as well as evaluation of the retroperitoneal spaces
and lymph nodes At the same time that the EOC
patient is being evaluated for the stage of the disease,
the surgeon also attempts to remove all visible tumors
from within the peritoneal cavity Additionally, the
sur-geon washes the peritoneal cavity several times with
sal-ine in order to remove as many tumor cells as possible
This procedure is termed cytoreductive surgery or
tumor debulking [70]
The stages (I-IV) of ovarian cancer are determined by
the extent of metastasis Stage I EOC is confined to the
ovaries whereas stage II affects other pelvic structures
In stage III, the disease has spread beyond the pelvis
into the upper abdominal cavity or into the draining
nodal beds irrespective of peritoneal based disease Stage
IV is defined as disease outside of the peritoneal cavity
and most commonly includes parenchymal liver lesions
or malignant pleural effusions Patients with stage I
dis-ease most commonly undergo bilateral oophorectomy,
hysterectomy, and surgical staging including peritoneal biopsies, omentectomy, and pelvic and aortic lymph node dissection In select cases of younger patients who wish to preserve fertility, only the affected ovary may be removed and a hysterectomy would not be performed [70] Chemotherapy treatment in early stage disease is dependent upon the grade of the tumor It is recom-mended that patients with advanced stage (II, III or IV) EOC undergo cytoreductive surgery to remove all visible tumor whenever feasible, followed by platinum and tax-ane based chemotherapy [70] Despite a high rate of initial remission, these patients have a high rate of recurrence (at least 50%) and overall poor survival Can-cer diagnosed in early stages has a much higher 5-year survival rate (Stage I: >90%, Stage II: 70-80%) compared
to cancer diagnosed in later stages (Stage III: 20-30%, Stage IV: <5%) [70] A major advance in the treatment
of ovarian cancer has come from intraperitoneal admin-istration of platinum and taxane agents instead of the more conventional intravenous delivery of these drugs [71-73] Of the 654 randomized patients included in one trial, the median survival for patients receiving intraperi-toneal cisplatin was 49 months compared to 41 months for the cohort receiving intravenous cisplatin [73] Increased cytotoxicity remains a major hurdle curtailing the efficacy of intraperitoneal chemotherapy [74] Treatment is made difficult for EOC patients because metastasis is acute and tumor cells exert immunosup-pressive effects The anatomical location of the ovaries within the peritoneal cavity facilitates metastasis because tumor cells can spread by sloughing off of the main tumor and binding to many organs in the vicinity, including the peritoneal cavity surfaces and the highly vascular omentum [75] This complicates treatment in that it is technically impossible to remove all cancerous cells during cytoreductive surgery The accumulation of peritoneal fluid in ovarian cancer patients also contri-butes to metastasis by aiding the flow of tumor cells within the peritoneal cavity Peritoneal fluid contains secretions from the tumor cells that have now been shown to contain many factors which aid in the inhibi-tion of the immune system in these patients [76-83] Furthermore, ovarian tumors also acquire resistance to chemotherapy Spheroids, or clumps of tumor cells (extremely common in the peritoneal fluid of EOC patients), have been shown to be more resistant to che-motherapy [84] De novo and acquired chemoresistance combined with expression of immunosuppressive factors makes it difficult to effectively treat ovarian cancer [85,86]
Tumorigenesis and Metastasis Tumorigenesis requires several genetic alterations, either somatic or inherited, that confer a selective growth
Trang 5advantage to the neoplastic cell population During
tumor development, initial random genetic alterations
result in a tumor cell population with a proliferative
advantage These tumor cells become the progenitors of
a clonal population that eventually dominates the tumor
mass Tumor progression is analogous to Darwinian
selection, with repeated mutations and subsequent
dom-inance of the daughter cell population via expression of
traits that confer a survival advantage [86]
A defining characteristic of a malignant epithelial
tumor is invasion beyond the basement membrane into
the surrounding stromal tissues For example, in breast
disease benign tumors such as fibrocystic lesions,
sclero-sis adenoma, and fibroadenoma are all characterized by
disorganization of the normal epithelial architecture
However, no matter how extensive this disorganization
may become, these benign lesions are always
character-ized by a continuous basement membrane that separates
the neoplastic epithelium from the stroma [87]
Malig-nant tumors are characterized by their ability to invade
through the basement membrane after which it is
impossible to determine how many cells have escaped
from the primary tumor and have established at
meta-static sites [88] Similar to malignant invasion some
non-cancerous cells can physiologically invade basement
membranes Common examples of this include
migra-tion of immune cells during an inflammatory response,
endothelial cells during an angiogenic response, and
tro-phoblasts into the endometrial stroma and blood vessels
to establish contact with the maternal circulation during
placentation The mechanisms used by these cells are
thought to be very similar to those used by invading
tumor cells [88,89] The difference between these
nor-mal functions and the invasion associated with tumor
cells is the lack of regulation seen in cancer The
mechanisms for the regulation of invasiveness are yet
undetermined Development of novel therapeutic agents
towards these factors could help treat inflammatory, and
angiogenesis disorders, as well as cancer formation [88]
Once a tumor is established metastasis may occur
While primary tumors are usually successfully
elimi-nated by surgical or chemotherapeutic means,
metas-tases are more difficult to detect and treat [89]
Metastases can cause death via paraneoplastic
syn-dromes, interference with the normal functioning of an
organ because of a growing lesion, or from
complica-tions related to treatment [89]
EOC was originally thought to be of the linear-clonal
model of metastasis, which states that a late stage clone
of the tumor acquires an additional genetic change that
enables metastatic progression [90] However, metastasis
may not be the final stage of clonal evolution during
tumor progression Some cells seem to have derived from
early stage clones in the primary tumor while others
derive from later stage clones This group supports a model in which primary ovarian cancers have a common clonal origin but become polyclonal with different clones
at both early and late stages of genetic divergence acquir-ing the ability to progress to metastasis [90]
The complexity of metastasis increases when one con-siders that each cancer type typically metastasizes to dif-ferent areas in the body This is termed the “seed vs soil” hypothesis which was first observed by Stephen Paget in 1889 [91] Referring to the tumor cell as the seed and a potential metastatic site as the“soil,” he sta-ted,“When a plant goes to seed, the seeds are scattered
in all different directions; but they can only live and grow if they land on congenial soil.” He hypothesized that this theory could be used to predict metastatic loca-tions for different cancers Different selective pressures exist in different organs and the tumor cells must adapt
to these environments Some of these pressures include hypoxia, presence of reactive oxygen species, or lack of nutrients Tumor cells must then alter their phenotype
in order to exist in environments with different selective pressures [92]
In ovarian cancer, the“seed vs soil” observation holds true as the most common sites of metastasis are within the peritoneal cavity Mesothelial cells that express mesothelin line the walls of the peritoneal cavity as well
as the organs within it We and others have shown that MUC16, present on the surface of cancer cells, binds readily to mesothelin [93,94] Recently, the binding site for MUC16 on mesothelin was characterized [95] This interaction is just one of the many that make the“soil”
of mesothelial cells within the peritoneal cavity an appropriate environment for ovarian cancer tumor cells
In order to efficiently metastasize, tumor cells must first detach from the primary tumor by downregulating adhesive molecules, then later upregulate adhesive mole-cules to attach again to the target site epithelium The initial step of detachment requires disruption of cell-cell adhesions, and this is facilitated by a loss of E-cadherin E-cadherin is tethered to the actin cytoskeleton, which plays a primary role in supporting cell-to-cell adhesions The disruption of the expression of E-cadherin can then lead to cells which can disseminate from the primary tumor Loss of E-cadherin function is necessary but not sufficient for an epithelial to mesenchymal cell type transition [95] Loss of E- cadherin has been seen in many types of cancers, such as breast, prostate, esopha-gus, stomach, colon, skin, kidney, lung, liver, and ovary [96,97]
After detachment from the primary tumor site, the next step of metastasis is to effectively invade into neighboring tissues Movement of the tumor cells through solid tissues requires the acquisition of pheno-types that allow cells to degrade the ECM and
Trang 6subsequently acquire forward propelling movements to
invade into these tissues [92]
Next, the tumor cells migrate into the circulation,
lymphatic system, or peritoneal space In EOC,
metasta-sis is facilitated by the clockwise flow of peritoneal fluid
The final steps of metastasis include arrest in the small
blood vessels of a distant organ, extravasation into the
surrounding tissue and proliferation at the secondary
site [92]
Immune Evasion
Patients with EOC often experience several periods of
remission and relapse of increasingly shortening periods
until their tumors become resistant to chemotherapeutic
treatment [98] Additionally, as the stages of cancer
pro-gress, patients exhibit progressively deficient immune
responses, which indicate that the tumor has developed
mechanisms to subvert the immune response and
sup-press immune surveillance [99] The importance of the
role of the immune system in the control and
elimina-tion of EOC is evidenced by a study that correlated the
5-year overall survival in EOC with the presence or
absence of tumor-infiltrating lymphocytes (TIL) (38% vs
4.5%, respectively) [100] There are several studies which
show that molecules from the tumor directly inhibit
immune cells We have now also demonstrated that
MUC16 protects the ovarian tumor cells by sterically
blocking the NK cells from forming immune synapses
with the cancer cells [101] High levels of shed MUC16
(sMUC16) are present in the PF of EOC patients and
this mucin binds to NK cells within the PF [76]
MUC16 binds specifically to the inhibitory receptor,
Siglec-9 on the surface of the NK cells (Belisle et al.,
paper submitted) Normally, NK cells in the peripheral
blood of healthy subjects have the phenotype 90% CD16
+
and 10% CD16- The CD16+ phenotype is associated
with activation and cytotoxicity, while the CD16-cells
release cytokines and are not cytotoxic [102] In the PF
of EOC patients, however, this ratio shifts to 60% CD16
+
and 40% CD16- Therefore, there are less cytotoxic
cells in the PF compared to the peripheral blood [76]
Other immune cell subsets can also be affected by
fac-tors within peritoneal fluid A study published in 2001
described a factor within PF that induced the loss of the
T cell receptor (TcR)-associated signal transducing
zeta-chain (CD3ζ) [81] They isolated this factor using
col-umn chromatography, gradient centrifugation, and mass
spectrometry and found that it was a 14 kD factor that
operated at the mRNA level [81] Webb and colleagues
have shown that CD1d antigen presentation to NKT
cells is inhibited by factors within the PF This effect
was dose dependent and CD1d specific [103] Another
study determined that supernatants from ovarian cancer
cell lines inhibited CD8+T cell proliferation and
function, as well as the cells’ ability to produce IFN-g IL-2R subunits g and b (but not a) were significantly suppressed as measured by flow cytometry [104] Our group has also described the presence of Decoy Recep-tor 3 (DcR3) in the peritoneal cavity of women with advanced EOC and that this molecule functions as a potent inhibitor of Fas-ligand mediated apoptosis a common regulatory mechanism of the normal immune system [80]
Tumor cells also produce ligands that can bind to activating receptors on immune cells and thus downre-gulate the expression of these receptors The ligands for activating receptor NKG2D are MHC class I-chain-related proteins A and B (MICA/MICB) and the UL16-binding proteins (ULBP-3) [105] NKG2D ligands are not expressed on normal, healthy cells and therefore the expression of NKG2D ligands is correlated with malig-nant transformation NKG2D receptor is expressed by all NK cells, CD8+T cells, most NKT cells, and a subset
of CD4+ T cells [105] When NKG2D binds to its ligands, it induces the cytotoxic activation and prolifera-tion of the immune cell However, MICA and MICB can be cleaved from tumor cells by tumor-associated mellatoproteinases, which leads to soluble MICA and MICB that can downregulate the expression of NKG2D [106] Wang and colleagues showed, using flow cytome-try, that serum from prostate and ovarian cancer patients contained high levels of soluble MICs and cor-related increased soluble MIC expression with decreased expression of NKG2D on T cells and a subset of NKT cells in these patients [107] Another study used immu-nohistochemistry to determine that tumor from 82 ovar-ian cancer patients showed expression of MICA, MICB, and ULBP-2, while none of these molecules was expressed by normal ovarian epithelium [108] Strong expression of ULBP-2 correlated with decreased infiltra-tion of T cells and poor prognosis [108]
Immunotherapy In EOC Most pre-clinical models of cancer immunotherapy indi-cate that such treatments work best in the setting of minimal volume, sub-clinical disease Thus it is thought that patients with minimal residual disease who clini-cally appear to be in remission are ideal candidates for immunotherapeutic strategies Immunotherapies may not be robust enough to eliminate the entire tumor when used alone, however; their use after surgery and chemotherapy may be useful to eliminate remaining sub-clinical tumor cells to prevent recurrence The high rate of clinical response to therapy and the subsequent high rate of recurrence in EOC after primary treatment
is evidence of a large number of women with sub-clini-cal disease at the completion of therapy These patients may offer an excellent setting for immunotherapy
Trang 7There are several immunotherapies that have been
targeted to MUC16 as well as mesothelin One such
immunotherapy, oregovomab, is an immunoglobulin (Ig)
I gG1k subclass murine monoclonal antibody that binds
with high affinity to circulating CA125 This antibody
complexes with CA125 and is taken up and processed
by APCs (antigen presenting cells) [109,110] Both a
humoral and cellular response are produced, as
demon-strated by the production of CA125 specific antibodies,
T-helper cells, and CTLs in patients who received
treat-ment [109,111,112] Survival was increased in patients
that mounted T-cell responses against CA125, however,
the most recent results from a phase III trial published
in January of 2009 stated that monoimmunotherapy
treatment with oregovomab resulted in no significant
difference in outcome compared to placebo [111]
Antibodies, designated 3A5 and 11D10, against the
tandem repeat sequence of MUC16 have been
conju-gated to the cytotoxic auristatin analogs
monomethy-lauristatin F and monomethymonomethy-lauristatin E [113,114]
These drug-conjugated antibodies have been utilized as
agents for chemotoxic immunotherapy resulting in an
improved therapeutic index against MUC16-expressing
OVCAR-3 tumors that were xenogenically grown in
mice [113]
Abagovomab (ACA125) is an anti-idiotypic antibody
against the MUC16 antibody OC125 and mimics the
antigenic epitope of MUC16 It serves as a surrogate
when given to patients In phase I and II trials, patients
that received abagovomab antibody developed
anti-anti-idiotypic antibodies (Ab3) and this correlated with
increased survival [115,116] Reinartz and colleagues
developed a fusion protein of ACA125 with interleukin
6 in order to stimulate ACA125 specific B cells [117]
This resulted in increased levels of Ab3 in patients who
received treatment
Mesothelin is normally expressed by mesothelial cells
that line the pleura, peritoneum, and pericardium It is
highly expressed by tumor cells associated with
pancrea-tic, ovarian, and lung adenocarcinomas as well as
malig-nant mesothelioma [118,119] Its normal function is
unknown and knockout mice show no abormalities
[120] However, we and others [93,94] have shown that
it binds to MUC16, which facilitates the metastasis of
ovarian cancer cells to the peritoneal cavity Agents that
would inhibit this interaction would be beneficial to
pre-vent metastasis in EOC patients A majority of patients
with serous epithelial ovarian cancer show increased
levels of serum mesothelin, making it a suitable target
for immunotherapies, considering its relatively low
expression in normal tissues [121] SS1P is a
recombi-nant immunotoxin consisting of an anti-mesothelin Fv
linked to a Pseudomonas exotoxin that mediates cell
killing Phase I trials have been completed with SS1P
and have shown anti-tumor activity in heavily treated patients [122] Pre-clinical studies in animal models have shown that treatment with SS1P has an increased effect when combined with chemotherapy [123]
MORAb-009 is a high affinity chimeric monoclonal IgG1/ with high affinity and specificity for mesothelin [124] This antibody both induces ADCC (antibody-dependent cellular cytotoxicity) against tumor cells that express mesothelin as well as blocks the MUC16/ mesothelin interaction [124,125] Phase I trials with MORAb-009 are underway with 11 patients, 6 with mesothelioma, 3 with pancreatic cancer, and 2 with ovarian cancer CRS-207 is another mesothelin cancer vaccine that utilizes Listeria monocytogenes as the vector Pre-clinical studies have shown this vaccine to elicit CD4+/CD8+ T cell mesothelin specific responses
in mice and cynomolgus monkeys A Phase I trial for CRS-207 is underway [123]
There are several other molecular candidates that are being investigated for immunotherapy against ovarian cancer Incubation of immune cells with ovarian cancer cells lead to generation of antigen specific T cells against THP-1 and other peptide epitopes of ovarian cancer [126] Other potential antigens for immunother-apy include p53, Her-2 and TPD52 Vaccination with Her-2 peptides along with measles virus fusion protein,
a promiscuous T cell epitope causes increased anti-tumor immune responses [127] Similarly, 66% of mice developing responses against TPD52 expressing prostate tumors were free of the cancer 85 days after tumor inoculation and were also able to resist a subsequent tumor challenge [128] The high expression of TPD52
by ovarian tumors provides hope that this strategy may also provide benefit to ovarian cancer patients
Autoantibodies against p53 are present in ovarian can-cer patients and their presence is associated with improved survival [129] In a phase II clinical study, patients vaccinated against specific p53 peptides showed proliferation of p53 specific T cells [130] These prolifer-ating T cells were immune competent and produced high levels of IFN-g A subset of the patients (2/20; 10%) developing p53-specific T cells showed evidence of stable disease as compared to the remaining cohort with clinical and biochemical evidence of progressive disease These data indicate that more research is required to produce effective immunotherapeutic approaches for the treatment of ovarian tumors
Conclusion Cytoreductive surgery followed by intense chemotherapy with platinum and taxol has become a standard approach for the treatment of EOC Therapy is espe-cially effective if the cancer is detected at early stage of progression Future advances in the management and
Trang 8cure of EOC will depend on development of novel
treat-ment modalities and diagnostic tests that can accurately
detect early stage low volume tumors While
chemother-apeutic approaches have been important in the
manage-ment of EOC, there is a growing sense in the field that
additional supportive therapeutic approaches will be
required for effective elimination of the cancer The
polyclonal nature of EOC ensures that therapeutic
approaches may not eliminate the entire spectrum of
cancer cells present in a patient Combinatorial
approaches that can result in direct cytotoxicity, prevent
tumor angiogenesis, inhibit cancer metastasis, and also
simultaneously increase the immunologic detection of
tumors may be required to eliminate the polyclonal
tumors Such a holistic approach will require delineation
of the molecular mechanisms that allow tumors to
metastasize, promote angiogenesis, and to circumvent
any effective immunological responses
The combined treatment strategies will benefit from
the development of diagnostic and screening tests To
date the “gold standard” for assessing the regression
and recurrence of EOC is the serum CA125 (MUC16)
assay However, this assay is limited in its scope
Devel-opment of novel proteomics based approaches for the
development of diagnostic tests hold great promise
However, even after intense research, successful
devel-opment of a proteomics-based diagnostic test has
remained elusive
Overall, significant hurdles still remain in the effective
diagnosis and treatment of EOC The significant
advances made in the molecular understanding of EOC,
development of murine models and novel
proteomics-based technologies, and the use of immune-proteomics-based
treat-ment approaches are likely to provide novel
opportu-nities for the effective management of EOC
Acknowledgements
Funding for this research was provided by grants from the Department of
Defense (#W81XWH-04-1-0102), Medical Education Research Council (MERC)
of the University of Wisconsin-Madison, charitable donation from Jean
McKenzie, and start-up funds from the Department of Obstetrics and
Gynecology to MSP.
Author details
1 Department of Biology, Augustana College, 2001 S Summit Ave, Sioux Falls,
SD, 57197, USA.2Department of Obstetrics and Gynecology, University of
Wisconsin-Madison, 600 Highland Ave, Madison, WI, 53792, USA.
Authors ’ contributions
JAAG, JPC, and MSP did the majority of the writing of this manuscript NC
and AK contributed by writing specific sections of this manuscript All
authors have read and approved this manuscript.
Competing interests
The authors declare that they have no competing interests.
Received: 10 November 2009 Accepted: 29 March 2010
Published: 29 March 2010
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